The present invention is generally directed to treating tumors, and more particularly to a method of inducing hypoxia in tumors through the use of a magnetic fluid.
Tumors consist of a core of hypoxic (low oxygen) cells surrounded by a mass of non-hypoxic cells. The hypoxic cells form up to 30% of the tumor and are due to the poor, inadequate blood vessels that are formed to feed fast growing tumor cells. In order for a tumor to grow beyond a certain size, the tumor cells need oxygen and nutrients. Therefore, tumors are dependent on their vasculature to transport oxygen and nutrients in the blood to their cells. The growth of new blood vessels in tumors is termed angiogenesis.
Traditionally, cancerous tumors are treated by excision, chemotherapy, radiotherapy, or a combination of the three. However, each of these treatments has various disadvantages. Excision is impractical with a diffuse mass and impossible if tumors are located in a surgically inoperable area. Both chemotherapy and radiotherapy are nonspecific and inefficient as they target and kill both cancerous and benign cells. There are also various side effects associated with chemotherapy, such as hair loss and nausea. In addition, many cancerous cells develop drug resistance during chemotherapy and tumors often remain resilient throughout radiotherapy.
It has been proven that radiotherapy and chemotherapy are less effective in regions of hypoxic cells in tumors. In fact, hypoxic cells are three times more likely to resist radiation treatment. If non-hypoxic tumor cells are killed using radiotherapy or conventional chemotherapy, the tumor's previously dormant hypoxic cells may cause regeneration resulting in a more malignant, aggressive and treatment-resistant tumor. Administration of artificial oxidizing agents (nitroimidazoles) in combination with radiotherapy or chemotherapy, breathing of carbogen (an oxygen-rich gas) in combination with radiotherapy or chemotherapy, and hyperthermia are known methods of killing hypoxic tumor cells.
Angiogenesis suppressant drugs, such as endostatin and angiostatin, have been developed to slow or completely stop tumor growth. However, these drugs must be genetically engineered for clinical research, are difficult to maintain active in large quantities, and exhibit low stability under ambient conditions. Most importantly, anti-angiogenesis drugs alone may not kill all cells.
Another technique for killing tumor cells combines blocking the transport of oxygen and nutrients in blood to the cells with chemotherapy drugs. This technique is called transcatheter chemoembolization and is used to treat cancers of the liver. In transcatheter chemoembolization, a catheter is placed in the artery that supplies the tumor with blood and chemotherapy drugs and tiny sponge particles are injected into the catheter. The chemotherapy drugs kill the tumor cells while the sponge particles decrease the blood flow to the tumor and cause it to shrink. However, liver cells are somewhat hypoxic and while this treatment kills tumor cells of the liver, it may not be effective in tumors located in other areas of the body. The technique also does not kill all tumor cells and there is a high probability of reoccurance.
Other typical tumor treatments occlude blood flow to the tumor. There are four major types of devices designed to occlude blood flow to tumors: “glue,” thrombosis producing particles, balloons, and coils. The term “glue” refers to compounds delivered to blood vessels which solidify on the walls of the blood vessels. These compounds typically solidify when they are exposed to electrolytes in the blood. Thrombosis producing particles are particles of polyvinyl alcohol, silicone polymer, proteins, glass, latex, silk suture material, or other materials which block blood vessels with diameters smaller than those of the particles. A balloon can be inserted into a blood vessel by a catheter or other means and then inflated to occlude blood flow in the vessel. Lastly, coils placed within a blood vessel present an obstacle to blood flow and induce blood clots thereon to stop blood flow.
However, all of these devices are subject to severe limitations. It is difficult to locate “glue” in a specific position as the cure rate of the “glue” varies. Thrombosis producing particles cannot block blood vessels with diameters larger than those of the particles, therefore, it is difficult to control the point of occlusion with thrombosis producing particles. Balloons may deflate or rupture the blood vessel and coils often fail to completely occlude blood flow. Complete occlusion might only be achieved with multiple coils and the use of multiple coils is costly and time consuming.
U.S. Pat. No. 5,646,185 discloses a method of treating a solid tumor including administering a compound which activates protein kinase C (PKC) to tumor such that the compound is directed to the hypoxic cells in the tumor. Compounds which activate PKC are selectively cytotoxic under hypoxic conditions. Suitable compounds which activate PKC include phorbol esters, diacylglycerols, and thapsigargin. The cells may be hypoxic either because of poor vascularization or the administration of a vasoconstrictive or vaso-occlusive agent. The vasoconstrictive agent may be a pharmaceutical vasoconstrictive compound such as an alpha adrenergic direct or indirect agonist. The vaso-occlusive agent may be a biodegradable or biocompatible vaso-occlusive agent, such as a cross-linked collagen, a cross-linked polyethylene glycol, a cross-lined polyactic acid, a cross-linked polyglycolic acid, or the like. Although compounds which activate PKC may be considered hypoxic drugs, this patent does not utilize magnetic fluids as the vasoconstrictive or vaso-occlusive agents.
Other forms of tumor treatment utilize magnetic fluids. Magnetic fluids are magnetic field responsive fluids containing magnetizable particles dispersed in a carrier liquid.
Two types of tumor treatments which utilize magnetic fluids are magnetic hyperthermia and magnetic drug delivery. U.S. Pat. Nos. 4,106,488; 4,303,636; 4,323,056; 4,545,368; 4,574,782; 4,662,359; 5,067,952; 5,108,359; 6,167,313 and 6,149,576 disclose magnetic hyperthermia, a process of passing an alternating magnetic field across a magnetic fluid in order to heat the particles within the magnetic fluid so that they destroy the tissue in their path. For example, U.S. Pat. No. 5,108,359 discloses a hemangioma treatment method comprising reducing the arterial blood flow to the hemangioma and administering a hard ferromagnetic substance to the hemangioma tissue wherein the hemangioma is under a magnetic field. Then the hemangioma is subject to an electromagnetic field of UHF frequencies or ultrasound energy as a hyperthermic treatment. In this patent, the hard ferromagnetic substance heats the tumor cells in the hyperthermic treatment. However, the success of magnetic hyperthermia has been hindered by the inability of current techniques to selectively heat many smaller visceral masses. It is also known in the art to chemically bind a drug to a ferrofluid, a type of magnetic fluid, and apply a magnetic field at the tumor site to direct and hold the drug at the tumor site (Lubbe, Cancer Res. 56: 4686 (1996)).
U.S. Pat. No. 5,236,410 discloses a tumor treatment method utilizing a ferrochemoembolizate. The arterial vessel that supplies the tumor is catheterized and a ferrochemoembolizate consisting of a magnetically hard ferromagnetic substance in a powder form, an oil medium, and an oil-soluble chemotherapeutic agent are injected into the catheter and consequently into the tumor. During injection, a local magnetic field is applied onto the tumor area. The injection lasts for about 1-5 minutes and the magnetic field is maintained for an extra 5-10 minutes. After 1-3 days, the tumor is also subjected to hyperthermia. Ultrahigh radio frequency electromagnetic field or ultrasonic waves are applied to the tumor to the temperature of 43.0°-43.5° C. for 5-45 minutes to ensure the death of the tumor cells. U.S. Pat. No. 5,236,410 also states that, in cases of large tumors it may be desirable to reduce blood flow with a metal coil in the tumor feeding blood vessel after administration of the chemoembolizate. However, in this patent the chemoembolizate alone does not ensure death of the tumor cells.
A method of treatment of hepatomas by the administration of a chemotherapeutic agent and ferromagnetic particles followed by hyperthermia is also known in the art (Sako M., Hirota S. Gan To Kagaku Ryoho, vol. 13, No. 4, pt. 2, 1618-1624 (1986)). A magnetic field acts to confines the chemotherapeutic agent and the ferromagnetic particles within the tumor.
In view of the drawbacks associated with present treatments, there is a need for a better technique for the treatment of tumor.